Production and characterization of mice transgenic for the A and B isoforms of human Fc gamma RIII

Fc gamma receptor (Fc gamma R) engagement is pivotal for many effector func tions of macrophages, polymorphonuclear neutrophils (PMN), and natural kill er (NK) cells. Mice transgenic for the A and B isoforms of human (h) Fc gam ma RIII on macrophages, PMN, and NK cells were constructed to permit the st udy of mechanisms and potential in vivo strategies to utilize the cytotoxic effector and antigen-presenting functions of cells expressing the hFc gamm a R. The present report characterizes the phenotypic and functional express ion of hFc gamma RIII in transgenic mice derived by crossing hFc gamma RIII A and hFc gamma RIIIB transgenic mice. Interleukin-2 (IL-2) induces hFc gam ma RIII expression by myeloid cells and their precursors, and these transge nic receptors promote in vitro cytotoxicity and anti-hFc gamma RIII antibod y internalization. Splenocytes from untreated and IL-2-treated hFc gamma RI IIA, hFc gamma RIIIB, and hFc gamma RIIIA/B mice exhibited enhanced in vitr o cytotoxicity toward HER-2/neu-overexpressing SK-OV-3 human ovarian carcin oma cells when incubated with the murine bispecific mAb 2B1, which has spec ificity for HER-2/neu and hFc gamma RIII. These results indicate that hFc g amma RIII transgenes are expressed on relevant murine cellular subsets, exh ibit inducible up-regulation patterns similar to those seen in humans, and code for functional proteins. hFc gamma RIII transgenic mice exhibiting spe cific cellular subset expression will permit the examination of strategies designed to enhance hFc gamma RIII-dependent immunological effector functio ns and will provide a model system in which to evaluate preclinically poten tial candidate molecules that recognize hFc gamma RIII for the immunotherap y of cancer.